Because obesity is a major risk factor for a wide array of diseases including type 2 diabetes (T2DM), cardiovascular disease (CVD) and cancer, the current obesity epidemic constitutes one of the greatest threats to global human health in the 21st century. Genetics and adult life style factors have traditionally been regarded as the primary determinants for the risk to develop obesity, T2DM and CVD. More recently epidemiological studies have demonstrated that adverse influences during early development (in particular altered nutrient availability during fetal life) increase the risk to develop diseas in adult life. Because almost two thirds of American women now enter pregnancy either overweight or obese, clinical studies linking obesity in pregnancy to development of the metabolic syndrome in children is particularly alarming. However, a major obstacle for progress in this area is the lack of understanding of the mechanisms linking the abnormal metabolic environment in the obese pregnant woman to the development of metabolic syndrome in her children. Unfortunately, currently available animal models of obesity in pregnancy do not reproduce key aspects of the human condition. There is therefore an urgent need for an animal model of obesity in pregnancy that is clinically relevant. To address this need, we submit this R24 proposal with the objective to thoroughly characterize a new mouse model of obesity in pregnancy and its links to the development of metabolic syndrome in the offspring. In pregnancy, we will focus on maternal metabolism, placental signaling and nutrient transport, fetal growth and metabolism (Specific Aim 1). Furthermore, the offspring will be carefully phenotyped with particular emphasis on offspring growth, body composition, metabolism, cardiovascular function and longevity (Specific Aim 2). In a hypothesis-generating unbiased strategy, we will employ cutting edge discovery approaches including proteomics, transcriptome expression studies and small transcriptomic (miRNA, snoRNA) sequencing. In addition, we will utilize well-established, yet advanced approaches to assess in vivo placental blood flow (microspheres), transplacental transport (Flexner technique), insulin sensitivity (euglycemic hyperinsulinemic clamp), and blood pressure (telemetry). This proposal is significant because it addresses a critical need for an animal model of obesity in pregnancy and it is expected to increase our mechanistic understanding of intrauterine programming of adult disease, which may lead to novel intervention strategies during pregnancy to prevent the development of obesity, T2DM, CVD and cancer.
Babies born to overweight and obese mothers have an increased risk of developing obesity, diabetes and CVD in childhood or in adult life, however the underlying mechanisms are unknown. We propose to develop a novel and unique animal model of maternal obesity that will contribute to a better understanding of how these conditions develop. This work may help us design new strategies for early intervention and treatment of diseases that are of major importance for public health.